Our long-term objective has been to develop a set of noninvasive techniques for studying the human retina. By applying novel techniques and current theories of phototransduction to the full-field electroretinogram (ERG), we have successfully developed widely-used noninvasive techniques for studying the global activity of the rod and cone receptors, as well as the rod bipolar cells. These indices of objective retinal function can be appropriate outcome measures for treatment trials with systemically-administered agents. However, many ongoing and anticipated clinical trials involving diseases of the receptors require localized measures of retinal function, such as the multifocal ERG and static automated perimetry, for evaluating treatment efficacy. These tests, however, are difficult to administer, time consuming, and not patient friendly, plus, as typically used, assess only cone function. Due to recent developments in retinal imaging, we can now relate these functional measures directly to underlying structure. We have been focusing our efforts on a new noninvasive technique for measuring the structure (anatomy) of the retina, frequency domain optical coherence tomography (fdOCT). This work, supported by the current grant, has benefitted from our novel quantitative approaches to assessing segmentation of retinal layers seen on fdOCT scans. As part of Aim 1, we evaluate and improve our fdOCT measures of disease related damage to the photoreceptors and test the efficacy of these measures in the clinic. This includes developing and evaluating new methods for quantifying fdOCT scans. We use these methods to test hypotheses about disease mechanisms, as well as models of disease progression. In addition, we propose to test the hypothesis that a particular fdOCT measure (i.e. the IS/OS contour) can provide a better measure of disease progression than current standard measures for diseases such as retinitis pigmentosa (RP). As part of Aim 2, we extend our approach to diseases of the macula, the region of greatest importance to normal visual function. Motivated by evidence that diseases of the macula may affect the rods first, we seek to determine the relationship between fundus perimetric measures of rod function and fdOCT measures of receptor integrity in patients with early age-related macular degeneration (AMD), geographic atrophy, and Stargardt disease. We will test the hypothesis that rod fundus perimetry and fdOCT are more sensitive to progression in these diseases than visual acuity or measures of the area of atrophy on fundus photography. The inherent variability in current functional measures of progression in RP and diseases of the macula is a substantial deterrent to efforts to develop effective treatments. Costs become prohibitive due to the large numbers of patients and extensive trial durations that are required. Determining the utility and validity of fdOCT in RP, and its relationship to measures of local rod- and cone-mediated function in macular disease, could profoundly enhance the feasibility of future clinical trials in these diseases. PUBLIC HEALTH RELEVANCE: Many retinal diseases cause blindness by attacking the photoreceptors while others attack post-receptor cells. We are developing noninvasive techniques for assessing the mechanisms by which a disease affects different retinal cells. These same techniques can enable the ophthalmologist to monitor the health of these cells and, thus the effectiveness of alternative treatments.